Diastolic function parameters are improved by the addition of simvastatin to enalapril-based treatment in hypertensive individuals

Objective: Diastolic dysfunction (DD) is a frequent condition in hypertensive patients whose presence increases mortality and whose treatment remains unclear. The aim of this study was to investigate in a prospective, double-blinded, placebo-controlled randomized design the additive effect of simvastatin on DD in enalapril-treated hypertensive patients with average cholesterol levels. Methods: Hypertensive patients with DD and LDL-cholesterol <160 mg/dL underwent a run-in phase to achieve a systolic blood pressure (SBP) <135 mmHg and diastolic blood pressure (DBP) <85 mmHg with enalapril. Hydrochlorothiazide was added when need to achieve blood pressure control. Four weeks after reaching the optimum anti-hypertensive regimen patients were randomized to receive 80 mg simvastatin (n = 27) or placebo (n = 28) for a period of 20 weeks. Echocardiograms were performed before and after treatment with measurement of maximum left atrial volume (LAV), conventional and tissue Doppler velocities in early diastole (E, e') and late diastole (A, a'). Results: After 20 weeks, the simvastatin group presented reduction in SBP (-4 +/- 2 mmHg, p = 0.02), increase in E/A ratio (1.0 +/- 0.05 to 1.2 +/- 0.06, p = 0.03) and decrease of LAV indexed to body surface area (24.5 +/- 0.9 to 21.1 +/- 0.8 ml/m(2), p = 0.048), as compared with placebo arm. No change in systolic function and no correlation between the E/A ratio, LAV and changes in blood pressure or lipid profile were observed. Conclusions: The addition of simvastatin to enalapril in hypertensive patients with average cholesterol levels improves parameters of diastolic function independently of changes in blood pressure or cholesterol. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Identification of SL addition trans-splicing acceptor sites in the internal transcribed spacer I region of pre-rRNA in Leishmania (Leishmania) amazonensis

Trypanosomatidae is a family of early branching eukaryotes harbouring a distinctive repertoire of gene expression strategies. Functional mature messenger RNA is generated via the trans-splicing and polyadenylation processing of constitutively transcribed polycistronic units. Recently, trans-splicing of pre-small subunit ribosomal RNA in the 5' external transcribed spacer region and of precursor tRNAsec have been described. Here, we used a previously validated semi-nested reverse transcription-polymerase chain reaction strategy to investigate internal transcribed spacer (ITS) I acceptor sites in total RNA from Leishmania (Leishmania) amazonensis. Two distinct spliced leader-containing RNAs were detected indicating that trans-splicing reactions occur at two AG acceptor sites mapped in this ITS region. These data provide further evidence of the wide spectrum of RNA molecules that act as trans-splicing acceptors in trypanosomatids.

Sea bream (Sparus aurata) intensive larval rearing : effects of microalgae and phages addition on the performance of the larvae

Máster Oficial en Cultivos Marinos. Trabajo presentado como requisito parcial para la obtención del Título de Máster Oficial en Cultivos Marinos, otorgado por la Universidad de Las Palmas de Gran Canaria (ULPGC), el Instituto Canario de Ciencias Marinas (ICCM), y el Centro Internacional de Altos Estudios Agronómicos Mediterráneos de Zaragoza (CIHEAM)

Organocatalytic asymmetric mannich-type reactions: an easy approach to optically active amine derivatives

The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives (Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and active agent against fungi (Scheme I, right). At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II). In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a broad range of substituents as R-group and excellent results, unprecedented for Mannich-type transformations (Scheme II). With the optimised protocol in hand we have extended the methodology to the other Mannich-type reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness of this novel protocol. The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III). Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with high level of diastereomeric and enantiomeric excess (Scheme III). Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source (Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields and enantiomeric excesses. Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines (Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were good for both procedures covering a broad range of α-amino phosphonic acid ester. During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block for the completion of the synthesis (Scheme VI).

Acqua: solvente elettivo in Organocatalisi e Biocatalisi

Water is a safe, harmless, and environmentally benign solvent. From an eco-sustainable chemistry perspective, the use of water instead of organic solvent is preferred to decrease environmental contamination. Moreover, water has unique physical and chemical properties, such as high dielectric constant and high cohesive energy density compared to most organic solvents. The different interactions between water and substrates, make water an interesting candidate as a solvent or co-solvent from an industrial and laboratory perspective. In this regard, organic reactions in aqueous media are of current interest. In addition, from practical and synthetic standpoints, a great advantage of using water is immediately evident, since it does not require any preliminary drying process. This thesis was found on this aspect of chemical research, with particular attention to the mechanisms which control organo and bio-catalysis outcome. The first part of the study was focused on the aldol reaction. In particular, for the first time it has been analyzed for the first time the stereoselectivity of the condensation reaction between 3-pyridincarbaldehyde and the cyclohexanone, catalyzed by morpholine and 4-tertbutyldimethylsiloxyproline, using water as sole solvent. This interest has resulted in countless works appeared in the literature concerning the use of proline derivatives as effective catalysts in organic aqueous environment. These studies showed good enantio and diastereoselectivities but they did not present an in depth study of the reaction mechanism. The analysis of the products diastereomeric ratios through the Eyring equation allowed to compare the activation parameters (ΔΔH≠ and ΔΔS≠) of the diastereomeric reaction paths, and to compare the different type of catalysis. While morpholine showed constant diasteromeric ratio at all temperatures, the O(TBS)-L-proline, showed a non-linear Eyring diagram, with two linear trends and the presence of an inversion temperature (Tinv) at 53 ° C, which denotes the presence of solvation effects by water. A pH-dependent study allowed to identify two different reaction mechanisms, and in the case of O(TBS)-L-proline, to ensure the formation of an enaminic species, as a keyelement in the stereoselective process. Moreover, it has been studied the possibility of using the 6- aminopenicillanic acid (6-APA) as amino acid-type catalyst for aldol condensation between cyclohexanone and aromatic aldehydes. A detailed analysis of the catalyst regarding its behavior in different organic solvents and pH, allowed to prove its potential as a candidate for green catalysis. Best results were obtained in neat conditions, where 6-APA proved to be an effective catalyst in terms of yields. The catalyst performance in terms of enantio- and diastereo-selectivity, was impaired by the competition between two different catalytic mechanisms: one via imine-enamine mechanism and one via a Bronsted-acid catalysis. The last part of the thesis was dedicated to the enzymatic catalysis, with particular attention to the use of an enzyme belonging to the class of alcohol dehydrogenase, the Horse Liver Alcohol Dehydrogenase (HLADH) which was selected and used in the enantioselective reduction of aldehydes to enantiopure arylpropylic alcohols. This enzyme has showed an excellent responsiveness to this type of aldehydes and a good tolerance toward organic solvents. Moreover, the fast keto-enolic equilibrium of this class of aldehydes that induce the stereocentre racemization, allows the dynamic-kinetic resolution (DKR) to give the enantiopure alcohol. By analyzing the different reaction parameters, especially the pH and the amount of enzyme, and adding a small percentage of organic solvent, it was possible to control all the parameters involved in the reaction. The excellent enatioselectivity of HLADH along with the DKR of arylpropionic aldehydes, allowed to obtain the corresponding alcohols in quantitative yields and with an optical purity ranging from 64% to >99%.

Materiali Politiofenici Otticamente Attivi

Much effort has been devoted in the recent years to the investigation of optically active polythiophenes characterized by the presence of a chiral moiety linked to the 3-position of the aromatic ring. In addition to their potential technological applications as materials for enantioselective electrodes and membranes, chiral poly(thiophene)s offer the possibility of studying the structural changes accompanying the transition from the disordered state by following the variation of their chiroptical properties by circular dichroism (CD). In solution of a good solvent, that kind of polythiophenes doesn’t display any optical activity arising from the presence of dissymmetric conformation of the backbone, as shown by circular dichroism (CD) spectra. When the macromolecules begin to aggregate, as it occurs e.g. by addition of a poor solvent, or lowering the solution temperature, or when the macromolecules are assembled in the solid state as thin films obtained by solution casting or spin coating, significant CD bands are observed in the spectral region related to the electronic absorptions of the aromatic polythiophene chromophore. These CD bands are indicative of a chiral macromolecule arrangement of one prevailing chirality. The synthesis of -substituted polythiophenes can be carried out starting from the corresponding -substituted mono- or oligomeric thiophenic monomers under regioselective or regiospecific conditions in order to minimize or avoid the formation of head-to-head dyads unfavourably affecting the presence of coplanar conformations of thiophene rings as a consequence of steric interactions between the side-chain substituents, both in solution and in the solid state. To this regard, non-symmetrically substituted monomers require therefore to perform the polymerization in the presence of highly demanding catalysts and reaction condition, whereas with symmetrically substituted oligothiophenic monomers containing the -substituents located far apart from the reacting sites, it is instead possible to obtain regioregular macromolecules by adopting more simple and economic polymerization methods, such as, e. g., the chemical oxidative polymerization with iron (III) trichloride. In order to verify how the polymer structure affects its optical activity, further poly-3-alkylthiophenes, substituted by an enantiomerically pure chiral alkyl group, namely poli[3,3”-di[2((S)-(+)-2-methylbutoxy)ethyl]-2,2’:5’,2”-terthiophene] (PDMBOETT), poli[3,3’di[2((S)-(+)-2-methylbutoxy)ethyl]-2,2’-bitiofene] (PDMBOEBT), poli[3,3””-didodecyl-4’,3”’-di(S)-(+)-2-methylbutyl-2,2’:5’,2”:5”,2”’:5”’,2””-quinquethiophene (PDDDMBQT) have been synthesized and characterized by instrumental techniques. The spectroscopic behaviour of thin films of poly(DDDMBQT) has been investigated in the solid state under different sample preparation procedures. It was also compared with the behaviour of polymers previously made. The experimental results are interpreted in terms of influence of the side-chain substituents on the extent of planarity of the polymeric chains and the formation of optically active chiral aggregates. In recent years conjugated block copolymers have received considerable attention. It is well known that conjugated block copolymers composed of two electronically different blocks can have morphologic and optical properties, that differ from those of their homopolymers. A recent study has also shown that the electronic properties and the supramolecular organization of one conjugated block can also be influenced by the other block. In order to study better this behavior, a new conjugated block copolymers, composed of a regioregular hydrophylic block and a regioregular hydrophobic block namely poli[3[2-(2-metossietossi)etossi]metiltiofene]-co- poli[3(1-octilossi)tiofene], has been synthesized and characterized.

Study of the components of quality in SO2-free wines obtained by innovative vinification protocols. Evaluation of the pre-fermentative addition of lysozyme and oenological tannins.

The research performed during the PhD candidature was intended to evaluate the quality of white wines, as a function of the reduction in SO2 use during the first steps of the winemaking process. In order to investigate the mechanism and intensity of interactions occurring between lysozyme and the principal macro-components of musts and wines, a series of experiments on model wine solutions were undertaken, focusing attention on the polyphenols, SO2, oenological tannins, pectines, ethanol, and sugar components. In the second part of this research program, a series of conventional sulphite added vinifications were compared to vinifications in which sulphur dioxide was replaced by lysozyme and consequently define potential winemaking protocols suitable for the production of SO2-free wines. To reach the final goal, the technological performance of two selected yeast strains with a low aptitude to produce SO2 during fermentation were also evaluated. The data obtained suggested that the addition of lysozyme and oenological tannins during the alcoholic fermentation could represent a promising alternative to the use of sulphur dioxide and a reliable starting point for the production of SO2-free wines. The different vinification protocols studied influenced the composition of the volatile profile in wines at the end of the alcoholic fermentation, especially with regards to alcohols and ethyl esters also a consequence of the yeast’s response to the presence or absence of sulphites during fermentation, contributing in different ways to the sensory profiles of wines. In fact, the aminoacids analysis showed that lysozyme can affect the consumption of nitrogen as a function of the yeast strain used in fermentation. During the bottle storage, the evolution of volatile compounds is affected by the presence of SO2 and oenological tannins, confirming their positive role in scaveging oxygen and maintaining the amounts of esters over certain levels, avoiding a decline in the wine’s quality. Even though a natural decrease was found on phenolic profiles due to oxidation effects caused by the presence of oxygen dissolved in the medium during the storage period, the presence of SO2 together with tannins contrasted the decay of phenolic content at the end of the fermentation. Tannins also showed a central role in preserving the polyphenolic profile of wines during the storage period, confirming their antioxidant property, acting as reductants. Our study focused on the fundamental chemistry relevant to the oxidative phenolic spoilage of white wines has demonstrated the suitability of glutathione to inhibit the production of yellow xanthylium cation pigments generated from flavanols and glyoxylic acid at the concentration that it typically exists in wine. The ability of glutathione to bind glyoxylic acid rather than acetaldehyde may enable glutathione to be used as a ‘switch’ for glyoxylic acid-induced polymerisation mechanisms, as opposed to the equivalent acetaldehyde polymerisation, in processes such as microoxidation. Further research is required to assess the ability of glutathione to prevent xanthylium cation production during the in-situ production of glyoxylic acid and in the presence of sulphur dioxide.

Asymmetric aminocatalysis: a modern strategy for molecules, challenges and life

The studies conducted during my Phd thesis were focused on two different directions: 1. In one case we tried to face some long standing problems of the asymmetric aminocatalysis as the activation of encumbered carbonyl compounds and the control of the diastereoisomeric ratio in the diastero- and enantioselective construction of all carbon substituted quaternary stereocenters adjacent a tertiary one. In this section (Challenges) was described the asymmetric aziridination of ,-unsaturated ketones, the activation of ,-unsaturated -branched aldehydes and the Michael addition of oxindoles to enals and enones. For the activation via iminium ion formation of sterically demanding substrates, as ,-unsaturated ketones and ,-unsaturated -branched aldehydes, we exploited a chiral primary amine in order to overcome the problem of the iminium ion formation between the catalyst and encumbered carbonylic componds. For the control of diastereoisomeric ratio in the diastero- and enantioselective construction of all carbon substituted quaternary stereocenters adjacent a tertiary one we envisaged that a suitable strategy was the Michael addition to 3 substituted oxindoles to enals activated via LUMO-lowering catalysis. In this synthetic protocol we designed a new bifunctional catalyst with an amine moiety for activate the aldehyde and a tioureidic fragment for direct the approach of the oxindole. This part of the thesis (Challenges) could be considered pure basic research, where the solution of the synthetic problem was the goal itself of the research. 2. In the other hand (Molecules) we applied our knowledge about the carbonylic compounds activation and about cascade reaction to the synthesis of three new classes of spirooxindole in enantiopure form. The construction of libraries of these bioactive compounds represented a scientific bridge between medicinal chemistry or biology and the asymmetric catalysis.

Sulfanyl Radical Addition to Alkynes: Revisiting an Old Reaction to Enter the Novel Realms of Green Chemistry, Bioconjugation, and Material Chemistry

In the last decade considerable attention has been devoted to the rewarding use of Green Chemistry in various synthetic processes and applications. Green Chemistry is of special interest in the synthesis of expensive pharmaceutical products, where suitable adoption of “green” reagents and conditions is highly desirable. Our project especially focused in a search for new green radical processes which might also find useful applications in the industry. In particular, we have explored the possible adoption of green solvents in radical Thiol-Ene and Thiol-Yne coupling reactions, which to date have been normally performed in “ordinary” organic solvents such as benzene and toluene, with the primary aim of applying those coupling reactions to the construction of biological substrates. We have additionally tuned adequate reaction conditions which might enable achievement of highly functionalised materials and/or complex bioconjugation via homo/heterosequence. Furthermore, we have performed suitable theoretical studies to gain useful chemical information concerning mechanistic implications of the use of green solvents in the radical Thiol-Yne coupling reactions.

Designed functional defects in colloidal photonic crystals: switching, biomonitoring and modified photoluminescence

Es werden zwei komplementäre "bottom-up" Methoden präsentiert, die den kontrollierten Einbau von "intelligenten" planaren Defekten in selbstorganisierte kolloidale photonische Kristalle (KPKs) ermöglichen. Die Defektschicht basiert auf einem funktionellen, nanometer-skalierten dünnen Film, der entweder durch schichtweise ("layer-by-layer") Selbstorganisation und Mikrokontakttransferübertragung oder durch Aufschleudern und einer KPK-Opferfüllung hergestellt wird. Die entwickelten Techniken gestatten die Integration von maßgeschneiderten dünnen Defektfilmen bestehend aus einer enorm großen Vielfalt an Materialien; sie sind kostengünstig und können im größeren Maßstab angewendet werden. Optische Untersuchungen zeigen einen engen, durch den Defekt hervorgerufenen Transmissionszustand in der photonischen Bandlücke. Die Defektwellenlänge hängt von der optischen Dicke der Defektschicht ab. Aktives Schalten der Defektwellenlänge wird erreicht, indem Defektschichten aus Makromolekülen hergestellt werden, die über externe Erreger wie Licht, Temperatur, Redoxzyklen und mechanischen Druck adressiert werden können. Die Ergebnisse der Untersuchungen sind im Einklang mit separat durchgeführten Ellipsometrie-Messungen und theoretischen "scalar wave approximation"-Berechnungen. Darüber hinaus werden KPKs mit funktionellen biomolekularen Defekten vorgestellt. Über Verschiebungen der Defektmode können DNA-Konformationsänderungen, die enantioselektive Einlagerung eines chiralen Antitumormedikaments sowie Enzymaktivitäten optisch beobachtet werden. Die Einlagerung von fluoreszierenden Farbstoffen und Quantenpunkten in Defekt-KPKs führt zu einer eindeutigen, durch die photonische Bandlücke und den Defektzustand hervorgerufenen Modifizierung der Photolumineszenz (PL)-Spektren. Schaltbare PL-Modifizierungen werden detektiert, wenn adressierbare Defekt-KPKs verwendet werden.

1,2-Additionen deprotonierter Alpha-Aminonitrile: Umgepolte Imine als vielseitige Synthesebausteine

Von aromatischen Aldehyden abgeleitete α-Aminonitrile können ohne die Anwendung von Schutzgruppen in α-Position deprotoniert werden, wenn keine lithiumhaltigen Basen verwendet werden. Ziel der vorliegenden Arbeit war es, die Reaktionen deprotonierter α-Aminonitrile mit Elektrophilen zu untersuchen. Die Addition von α-Aminocarbanionen an Imine führt unter intramolekularer Eliminierung von HCN zu Endiaminen, die sich in einer Eintopfsynthese abhängig von der Aufarbeitung in 1,2-Diamine oder 1,2-Diimine umwandeln lassen. Die nach Oxidation durch Luftsauerstoff erhaltenen Diimine können mit dem Reduktionsmittel BH3·THF diastereoselektiv reduziert werden. Es hat sich hier gezeigt, dass durch Zugabe einer katalytischen Menge an NaBH4 hauptsächlich die syn-Diamine erhalten werden, der Zusatz von Phthalsäure wiederum liefert bevorzugt die anti-Produkte. In beiden Fällen wird das Produkt in quantitativer Ausbeute erhalten. So konnte also eine effektive diastereoselektive Reduktionsmethode entwickelt werden, die eine freie Wahl der syn- oder anti-Konfiguration ermöglicht. Um enantiomerenreine 1,2-Diamine zu erhalten, wurden verschiedene Methoden getestet. Sowohl auxiliargesteuerte Synthesen mit einem N-Glycosyl-Aminonitril oder mit chiralen Sulfinyliminen als auch die Reduktion durch chirale Borverbindungen (CBS-Katalysatoren, Triacyloxyborhydrid oder Diisopinocamphenylboran), Transferhydrierungen mit chiralen Difluortitanocen-, Noyori- oder Organophosphat-Katalysatoren sowie enantioselektive Hydrierungen mit chiralen Übergangsmetall-katalysatoren waren jedoch nicht erfolgreich. Die Umsetzung der 1,2-Diimine mit Chlormethylethern oder -estern liefert die entsprechenden unsymmetrischen Imidazoliumsalze. Diese konnten zu N-heterocyclischen Carbenen deprotoniert und erfolgreich als Liganden in Suzuki- und Heck-Reaktionen eingesetzt werden. Durch die 1,2-Addition α-deprotonierter Streckerprodukte und anschließende Reduktion im Eintopfverfahren konnten 1,2-Aminoalkohole in mäßigen bis guten Ausbeuten dargestellt werden. Die Umsetzung von α-Aminocarbanionen mit N-Acyliminen erlaubt zudem die Synthese tetrasubstituierter Imidazole und trisubstituierter Oxazole in drei beziehungsweise vier Stufen: Die zunächst gebildeten α-Amino-α-acylaminopropionitrile können isoliert und in Gegenwart von Base einer Retro-Strecker-Reaktion unterworfen werden. Abhängig vom Substitutionsmuster schließt sich in manchen Fällen nach der Eliminierung von HCN direkt die Cyclisierung zum Imidazol an. Nicht cyclisierte Intermediate lassen sich durch Dehydratisierung mit PCl5 zu Imidazolen umsetzen, aber auch unter sauren Bedingungen zu α-Acylaminoketonen hydrolysieren, welche wiederum durch Einwirkung von PCl5 in Oxazole überführt werden können. Auf diese Weise wurden Imidazole und Oxazole in moderaten bis hohen Gesamtausbeuten hergestellt.

Imine von Formyl-[2.2]paracyclophanen und ihre Anwendung in der enantioselektiven Katalyse

Kohlenhydrate wurden bislang nur selten zur Darstellung chiraler Liganden verwendet. Sie gelten als zu polyfunktionell und konformativ zu flexibel, um daraus mit vertretbarem Aufwand Liganden zu synthetisieren, die die Anforderungen an ein leistungsfähiges Katalysatorsystem - die spezifische Komplexierung des Metalls in einer konformativ möglichst rigiden Umgebung - erfüllen.rnDas Element der planaren Chiralität erwies sich in vielen asymmetrischen, katalytischen Prozessen als entscheidend für die Erzielung hoher Enantioselektivitäten.rnDie vorliegende Arbeit baut auf den Kohlenhydratliganden-Synthesen mit Glycosylaminen auf, die über geeignete komplexierende Zentren verfügen, um damit andere als die bisher mit Kohlenhydraten bekannten enantioselektiven Katalysen durchführen zu können. Zur Synthese stickstoffhaltiger chiraler Verbindungen haben sich besonders perpivaloylierte Glycosylamine vom Typ des 2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosylamins bewährt. Im Rahmen dieser Dissertation wurden Schiff-Basen aus pivaloyliertem Galactosylamin bzw. verschiedenen anderen Galactosylamin-Bausteinen als chiralem Rückgrat, und einem Aldehyd auf der Basis von planar chiralem [2.2]Paracyclophan dargestellt. Die neuen N-Galactosylimine wurden außerdem in asymmetrischen Ugi-Reaktionen und in Tandem Mannich-Michael-Reaktionen zu N-Galactosyl-dehydropiperidinonen untersucht. Bei der Spaltung der dargestellten N-Galactosylimine von Paracyclophan-aldehyden unter mineralsauren Bedingungen sollten die entsprechenden mono- und di-substituierten Formyl- [2.2]paracyclophane in enantiomerenreiner Form erhalten werden. Die erhaltenen Verbindungen wurden als potentielle N,O-Liganden in der asymmetrischen Strecker Reaktion, in die enantioselektiven Epoxidierungen und in der Addition von Diethylzink an aromatische und aliphatische Aldehyde untersucht.rn

Synthese cyclischer Peptide und von Kohlenhydraten abgeleitete Katalysatoren zur enantioselektiven Darstellung von Cyanhydrinen

Der Suche nach neuen Wirkstoffen für den chemischen Pflanzenschutz kommt insbesondere vor dem Hintergrund der steigenden Weltbevölkerung und weniger zur Verfügung stehenden kulturfähigen Ackerflächen eine stetig wachsende Bedeutung zu. Ziel dieser Arbeit war die Synthese von cyclischen Peptiden und Depsipeptiden, die aufgrund ihrer biologischen Aktivität als potentielle Insektizide für den chemischen Pflanzenschutz in Frage kommen. Darüber hinaus sollten von Kohlenhydraten abgeleitete Katalysatoren zur enantioselektiven Cyanhydrinsynthese entwickelt werden, um einen leichten Zugang zu den Bausteinen der Depsipeptide zu ermöglichen. Als vielversprechender Naturstoff mit insektiziden Eigenschaften gilt das cyclische Pentapeptid Cycloaspeptid E, dessen Totalsynthese in 10 Stufen mit einer Gesamtausbeute von 25% erreicht wurde, sodass die Verbindung für biologische Tests bereitgestellt werden konnte. Zusätzlich gelang die Kristallisation der Verbindung, was eine Röntgenstrukturanalyse ermöglichte. Ein Derivat von Cycloaspeptid E sollte 2-Aminonicotinsäure anstelle von Anthranilsäure enthalten. Die Synthese dieser Verbindung wurde auf drei Wegen versucht. Dabei zeigte sich, dass es bei einer zur Totalsynthese des Naturstoffs analogen Strategie zur quantitativen Bildung eines Diketopiperazins kommt. Auf den anderen Routen ließ sich entweder ein Kupplungsschritt nicht realisieren, oder die Verbindung erwies sich unter den gewählten Bedingungen als instabil. Die Darstellung eines 2-Aminonicotinsäure-Derivats von Cycloaspeptid E bleibt daher weiterhin ein ungelöstes Problem, das weiterer Forschung bedarf. Verticilid A1 ist ein cyclisches Depsipeptid, das aufgrund seiner Bindungsfähigkeit an den Ryanodinrezeptor von Insekten, als Leitstruktur für die Suche nach neuen Insektiziden von Interesse ist. Um zu untersuchen, wie wichtig die Esterbindungen im Molekül für die biologische Aktivität sind, sollte das entsprechende Amid-Derivat und das Cyclodepsipeptid mit nur zwei statt vier Esterbindungen hergestellt werden. Hierbei zeigte sich, dass eine zur Darstellung von Verticilid A1 analoge Syntheseroute zu einer ausgeprägten Epimerisierung führt. Eine lineare Synthese der Derivate endet in der Bildung des Diketopiperazins. Weiterhin wurden zwei neue, zueinander pseudoenantiomere Vanadium(IV)-Katalysatoren auf Basis von D-Glucose einerseits und L-Xylose andererseits dargestellt. Diese lassen sich in fünf bzw. 14 Stufen synthetisieren und liefern in der enantioselektiven Katalyse von Mandelsäurenitril Enantiomerenüberschüsse von 89% bzw. 91% bei hohen Ausbeuten. Zusammenfassend lässt sich feststellen, dass im Rahmen dieser Arbeit die Totalsynthese von Cycloaspeptid E erfolgreich durchgeführt wurde, und die Syntheseversuche von weiteren cyclischen Peptiden wichtige Erkenntnisse für weitere Synthesen lieferten. Mit den beiden hergestellten Vanadium(IV)-Komplexen wurden zwei potente, auf Kohlenhydraten basierende Katalysatoren für die enantioselektive Synthese von Cyanhydrinen entwickelt.